Cell membranes are central elements in the signal transmission machinery of all higher life forms. It is therefore widely accepted that A? oligomer interactions with membranes play an important role in Alzheimer's pathogenesis. Yet, a molecular understanding of A? neurotoxicity in AD is still missing to date. By the concerted use of biophysical experimentation and theory/simulation, this program project (M. L"sche, Director) will provide molecular-scale information on A? oligomer interaction with membranes, transformations of peptide aggregate states and their impact on membrane nanostructure, and the effect of these factors on membrane embedded ion channels. The program consists of two Cores and three Research Projects. Cores A and B provides resources for the administration of the Program Project (Core A;M. L"sche, PI) and for peptide synthesis and immuno-reagents in the form of oligomer-specific antibodies (Core B: C. G. Glabe, PI). Research Project 1: Electrophysiology of A? Oligomer Interaction with Conductance Mechanisms in Cells and BLMs (J. E. Hall, PI). The Irvine group will measure electrogenic responses of free-standing membranes with well-defined chemical compositions and of cell membranes to A?, and will develop models of the interactions. Project 2: Structural and Functional Investigations of A? Oligomer Interaction with Synthetic Membranes (M. L"sche, PI). Sparsely tethered bilayer lipid membranes (stBLMs) are used to characterize molecular interactions, constitutional changes, and antibody interaction with membrane-bound A? (neutron reflection at NCNR;complementing electrochemical and optical techniques at Carnegie Mellon, CMU). Membrane reconstitution protocols for stBLMs will also be developed and the impact of A? oligomers on membrane-embedded KcsA will be determined. Project 3: Simulation of A? Oligomer Interaction with Membranes (M. Deserno, PI). Coarse-grained simulations of A? oligomers and membranes at CMU will be developed to investigate structural transformations of peptide and aid experimental data interpretation. Collaborations: (1) Membrane Channel Biophysics (J. A. Mindell, PI). The NINDS lab has an active research program on ion channels and will provide know-how on KcsA membrane reconstitution. (2) Electrochemical Spectroscopy of Tethered Bilayers (G. Valincius, PI;Institute of Biochemistry, Vilnius, Lithuania). The group supports the PPG with their expertise in electrochemical impedance spectroscopy (EIS) in a subcontract. REVIEW OF INDIVIDUAL COMPONENTS CORE A - ADMINISTRATIVE CORE;Dr. Mathias L"sche, Core Leader (CL) DESCRIPTION (provided by applicant): This administrative core provides assistance and resources to the Program Projects in all relevant administrative issues.